Effective pain control continues to be a major challenge for clinicians and basic scientists, as the lack of efficacy and/or dose-limiting toxicity of existing pharmacotherapies drive intensive efforts to discover novel analgesic strategies. Studies conducted and published during the previous iteration of this award have contributed to an accumulating body of evidence supporting a nicotinic cholinergic approach to pain management. Notably, prototypical nicotinic analgesic agents have been shown to be antinociceptive in animal models of both inflammatory and neuropathic pain. However, the appreciable CNS toxicity of these agents represents a significant obstacle in realizing this otherwise promising avenue of pain control. In this regard, the preliminary data presented in the present renewal application, taken together with the literature cited, strongly supports our working hypothesis that peripheral nicotinic acetylcholine receptors (nAChRs) are capable of mediating antinociception in response to certain nicotinic agonists. We propose to test this hypothesis by addressing the following specific aims: 1) To quantify and pharmacologically characterize the peripheral antinociceptive effects of nicotinic agonists in animal models of pain. 2) To identify the sensory neuronal nAChR subtypes that are activated to produce peripheral antinociception and inhibit nociceptor activity. 3) To define the cellular mechanisms that underlie the inhibition of nociceptor activity by nicotinic agonists. 4) To evaluate the effects of chronic nicotine treatment on sensory neuronal nAChR expression and nicotinic agonist-induced antinociception. The integrated, multimethodological studies proposed here should help to elucidate peripheral mechanisms of nicotinic analgesia. Such an understanding would provide important information for a rationale to develop a nicotinic cholinergic class of analgesic therapeutics that may have improved efficacy over current treatments without the attendant, CNS-mediated toxicities.